The androgens are responsible for the primary and secondary sexual characteristics in the male. Among their many other functions, the androgens have a strong anabolic effect on protein metabolism with pronounced muscular development and increased muscular strength. It also imparts a general feeling of well-being to the individual.
Scientists and medical researchers took advantage of these particular features of the androgens, and began in the 1950's experimenting with the androgenic-anabolic steroids, which are the synthetic analogues of the male hormone testosterone, the main androgen in the body, with a view to improve muscle strength and, at the same time, to avoid all the androgenic side effects, especially the virilizing and masculinizing effects in the female. However, it is impossible to dissociate the anabolic effect from the androgenic side effect in all the synthetic androgenic-anabolic steroids. Despite this fact, many athletes have little hesitation in taking the androgenic-anabolic steroids in order to achieve a winning edge over their competitors. The use of this group of drugs is approaching epidemic proportions, and many athletes are beginning to use these drugs as early as their high school days.
At the present time, the use of androgenic-anabolic steroids in athletes is still very controversial, and is not recommended by the medical profession for two reasons. Firstly, it is still uncertain whether these steroids do in fact improve athletic performance. Secondly, and more important, it is still to be determined to what extent these drugs may be harmful to the athletes.
There are conflicting reports relating to the efficacy of the androgenic-anabolic steroids in improving athletic performance. While there are many studies suggesting that these steroids do not improve athletic performance, many athletes are convinced that these steroids not only enhance their athletic performance, but also convey a general sense of well-being to the individual. This sense of well-being allows them to fit into a tighter practice schedule, thus enhancing their performances. There are also reports suggesting that these steroids are responsible for many of the record-breaking performances. The controversy relating to the use of the androgen-anabolic steroids goes a step further because of the potential risks involved, especially when these drugs are administered on a long term basis.
Briefly, suspected side effects of the androgenic-anabolic steroids include various hepatic abnormalities (for example, abnormal liver function tests, intrahepatic structural changes, malignant liver tumors, etc.), changes in cardiovascular risk factors with a change in lipoprotein cholesterol level and hypertension, endocrinology effects (for example, sterility, testicular atrophy and gynaecomastia in the male and masculinization, disturbances in the menstrual period, virilization including hirsutism and deepening of the voice in the female) and psychological changes including mood changes and changes in libido.
Present evidences suggest that many of the side effects of the androgenic-anabolic steroids are reversible once the drugs are discontinued. However, the side effects after long term administration, especially if high dosages are taken, are not so clear. Serious side effects, like hepatomas, though rare, can be rapidly fatal and are especially worrying. This is enough to alarm the scientific and medical world to impose a ban on the use of these steroids in competitive sports.
The reason why administration of these androgenic-anabolic steroids leads to such untoward effects is not known. A close parallel is the administration of estrogens in the female with the danger of developing cervical cancers and other adverse effects. A possible explanation is that the administration of exogenous hormones tends to upset the homeostasis of the body system, and such derangement eventually leads to the development of such side effects.
It is interesting to note that, in the body, the androgens in fact include a number of similar and related compounds, and so are the estrogens. But it is not known why nature should decide that such an arrangement should be necessary, since their functions in the body are very similar. A possible answer is that it is related to the feedback mechanism of the androgens to the gonadotropic function of the pituitary, whose true nature is still not completely known to medical science. Administration of a single androgen may therefore upset the delicate balance of the others, resulting in a derangement of the homeostasis of the body, with the consequence of developing the adverse effects.
It is also known that the plasma androgen level varies through a wide range of about 0.2 to 1 microgram per dl in the normal males. The reason why a relatively high level of natural androgens in the body will not produce any side effects is probably due to the fact that the relative proportions of the different androgens are well balanced, being regulated by the autoregulatory functions of the body in a very refined and delicate manner, so that the feedback mechanism to the pituitary is not disturbed.
If the range of the normal androgen level is so wide, maybe it is appropriate to know the optimum androgen level in the body; or, indeed, whether the optimum level is ever reached in a normal individual. It seems certain that the optimum level varies in different individuals. As to whether an optimum level of androgen is reached in normal individuals, there are evidences to show that it is not. For example, most athletes believe that administration of androgens will improve their strength and performance, together with an increase in muscle bulk, though this increase in muscle bulk is much less than in the replacement therapy with androgens in patients with hypogonadism. And one possible conclusion that can be drawn from this particular observation is that while there is a definite deficiency of androgens in hypogonadism, it may also be possible that there is a relative deficiency of androgens in many seemingly normal individuals. Otherwise, there is no good reason why administration of additional androgens will lead to further increase in the muscle bulk.
The above description and reasoning suggest strongly that there is a certain degree of deficiency of androgens in most seemingly normal individuals. But to make up the deficiency by administering exogenous androgens, especially over a prolonged period of time, will necessarily lead to adverse effects due to the disturbance of the homeostasis and the feedback mechanism, as explained above. This is a tricky situation and the solution cannot be found easily.
It is clear from the above argument that side effects will not and cannot be avoided as long as exogenous steroids are administered. The only apparent solution is to depend on the auto-regulatory system of the body to synthesize the optimum level of the androgens as is required for a particular individual, so that the body can function at its best.
As explained in copending patent application U.S. Ser. No. 07/580,019 relating to the treatment of acne vulgaris, at least 90% of the population will develop acne vulgaris sometime in their life. The development of acne vulgaris is indicative that there is a deficiency of pantothenic acid in the form of acetyl-CoA. Due to the complexity of the body functions, the absence of acne vulgaris in the 10% does not necessarily mean that there is no deficiency in pantothenic acid, only that the deficiency may present itself in other forms. Thus, it seems that most people, if not all, will have some form of deficiency of pantothenic acid in the form of acetyl-CoA. All steroidal compounds are synthesized from acetate units in the form of acetyl-CoA, so that a deficiency in acetyl-CoA will necessarily affect the synthesis of the sex hormones, be it the androgens or the estrogens, and the level of these hormones will not be at their optimum level. In accordance with the present invention, administering of pantothenic acid as replacement for steroidal compounds will help to reverse the situation completely. Through the auto-regulatory function of the body, all the steroidal hormones will be synthesized to their optimum level, and the desired optimum level of the androgens are achieved, resulting in the best anabolic effect possible without any of the side effects being experienced. The ideal situation is thus achieved.
As another aspect of this invention, steroids are widely used in a great variety of clinical conditions to alleviate symptoms of various diseases. Steroids, in this context, include all the corticosteroids secreted by the adrenal cortex and all the synthetic steroid analogues of cortisol with similar actions. However, aside from their use as replacement therapy, in situations where the body fails to secrete an adequate amount of natural steroids, the use of synthetic steroids in clinical practice is empirical. The mechanism is never adequately explained, and their use is never curative in the sense that it is not directed towards the etiology of the disease process, but is merely palliative. The use of steroids has the added disadvantage in producing a lot of very grave undesirable effects, particularly when used on a long term basis, though a short course of a few days is unlikely to produce any serious side effects. Despite the undesirable effects, steroids are powerful drugs in symptomatic treatment, so that in many instances their use is reserved as a last resort when all other forms of medical treatment fails. To minimize the side effects, the dosage prescribed is always kept to the minimum.
Goodman and Gilman, The Pharmacological Basis of Therapeutics, Sixth Edition, Macmilan Publishing Co., Inc., p. 1489-1492, presents a brief outline of important uses of steroids in clinical practice for the treatment of various clinical conditions or diseases as set out below.
Rheumatism and arthritis, particularly rheumatoid arthritis and osteoarthritis.
Rheumatic carditis.
Some form of nephrotic syndrome attributable to systemic lupus erythematosus.
The group of diseases called collagen diseases or connective tissue diseases.
Allergic diseases such as hay fever, serum sickness, urticaria, contact dermatitis, drug reactions, bee stings, angioneurotic edema and anaphylaxis.
Bronchial asthma, particularly chronic bronchial asthma.
Some forms of ocular diseases. Mainly used topically for diseases of the outer eye and anterior chamber. Posterior chamber diseases require systemic administration.
Skin diseases. Maibach and Stoughton have divided 20 dermatological disorders that respond to topical corticosteroids (see, Topical Corticosteroids, Med. Clin. North Am., 1973, vol. 57, 227-233.)
Some forms of diseases of the intestinal tract, e.g., celiac sprue, and crohn's disease.
Cerebral edema that is associated with tumors.
Some forms of malignancies, e.g., lymphomas, acute lymphocytic leukemia, carcinoma of the breast and in combination chemotherapy in association with alkylating agents such as cyclophosphamide.
Some forms of liver diseases, e.g., various types of hepatitis and cirrhosis.
Miscellaneous Diseases including sarcoidosis, thrombocytopenia, hemolytic anemias and organ transplantation.
In all these conditions, the use of steroids is entirely empirical, and even if the dosage is kept to the minimum, over a prolonged period of time, the side effect is still considerable. The more significant side effects can be summed up as follows:
Suppression of pituitary-adrenal function. PA1 Fluid and electrolyte disturbances. PA1 Hyperglycemia and glycosuria. PA1 Increased susceptibility to infections. PA1 Bleeding or perforated peptic ulcers. PA1 Osteoporosis. PA1 A characteristic myopathy. PA1 Behavioral disturbances. PA1 Posterior subcapsular cataracts. PA1 Arrest of growth. PA1 Cushing's habitus, consisting of "moon face", "buffalo hump", enlargement of supraclavicular fat pad, "central obesity", striae, ecchymoses, acne, and hirsutism.
Since steroid treatment is empirical, one very pertinent question is whether the action of the steroids is indeed due to the steroids themselves. This question is not odd and seems all the more reasonable since the range of action of steroids is so wide, from arthritis to allergy, from connective tissue diseases to asthma, from skin disorders to inflammatory diseases and others. It is not only amazing but intriguing and there are few other drugs having a similar wide range of action. With such a wide range of action, it is unlikely that it will act through certain target receptors, and some other explanations must be sought.
It is postulated that the action of the administered steroids in all these disease processes is not exerted through the steroids themselves, but that these administered steroids are in fact only sparing the raw material for steroid synthesis, and that it is the raw material for steroid synthesis that is actually doing the healing work. As is known, the steroids are synthesized from units of acetates derived from acetyl-Co A. And it is the acetyl-Co A, or rather, Coenzyme A, that is doing all the healing work. Coenzyme A is unique among all the coenzymes of the body in that it is the only coenzyme to stand in the crossroad of the final common pathway of carbohydrate, fat and protein metabolism, and is the key precursor in the synthesis of many different lipids. And the significance of Coenzyme A in lipid synthesis is even more impressive when it is known that most cell membranes contain about 40% of lipid, and that cholesterol, the precursor of fecal sterols, bile acids, and the steroid hormones, is synthesized from units of acetate derived from acetyl-Co A. A deficiency in Coenzyme A thus has the potential of extensively affecting the biochemical reactions in the body, depending on other concommitant conditions.
Steroids are peculiar in the sense that they are not stored in the body, so that they have to be synthesized almost continuously. And steroids are also essential for survival. For these two reasons, the steroids have to be synthesized continuously, under any condition, even when the body is deficient in acetyl-Co A, which, for practical purposes, is equivalent to a deficiency in Coenzyme A. This means that steroid synthesis has the privilege of claiming priority for units of acetyl-Co A in case of shortage at the dispense of other biochemical reactions, even though the derangement of these other biochemical reactions will, in the long run, lead to other forms of illnesses, which may be fatal. The body is concerned with the immediate survival rather than the distant future, and these reactions are sacrificed in preference to steroid synthesis.
As has been explained in copending U.S. patent application Ser. No. 07/580,019 and U.S. Pat. No. 5,039,698, a deficiency in Coenzyme A through a deficiency in pantothenic acid is very common. In such a deficiency state, all the metabolic processes that go through the crossroad of the final common metabolic pathway will have to compete with each other for the limited supply of Coenzyme A. Since steroid synthesis is obligatory, it becomes compelling to curtail other less urgent metabolic processes. The final clinical presentation will depend on which metabolic process is affected most. If, however, in a situation where an exogenous steroid is administered, making steroid synthesis no longer mandatory for the time being, the activities of the acetyl-Co A related to steroid synthesis will be temporarily withheld, making available Coenzyme A for other metabolic processes that are urgently in need of the participation of Coenzyme A. This will lead to a temporary relief of the symptoms of the pathological process, which actually represents a particular derangement of a certain metabolic process.